Agents capable of facile penetration into the CNS, and subsequent inhibition of acetylcholinesterase (AChE) and/or direct, selective M1-muscarinic receptor stimulation may be efficacious in the treatment of senile dementia of the Alzheimer type (SDAT). One such agent, physostigmine - a relatively lipid soluble AChE inhibitor, has demonstrated weak but significant efficacy in the treatment of SDAT. Rapid metabolic hydrolysis of the drug's carbamate ester is believed responsible for the variability in its clincal efficacy. The H2-antagonist, ranitidine, demonstrates significant inhibition of AChE at near therapeutic concentrations IC50 = 2.35 x 10-6 M, human erythrocyte AChE). The polarity of its diaminonitroethene group, however, prevents its significant absorption into the CNS. Preliminary work has demonstrated that relatively lipid soluble analogues of ranitidine retain significant AChE inhibitory activity. We propose to synthesize 34 additional analogues of ranitidine in an attempt to increase its AChE inhibitory activity and lipophilicity. The development of compounds with potentially, long metabolic half-lives and selective M1-muscrinic agonist activities is a secondary objective. AChE inhibitory and muscarinic binding assays will be performed utilizing conventional assays. Compounds found to be active AChE inhibitors will be evaluated for their ability to bind M1- muscarinic receptor sites. Compounds which actively bind M1- muscarinic receptor sites will be further evaluated for M1/M2 selectivity.